Dose recommendations: A tough pill to swallow

Paracelsus, a 16th-century physician, apparently once stated, “All things are poison, and nothing is without poison; only the dose permits something not to be poisonous.” With the plethora of prescription medications now available, this statement may ring more true today than 500 years ago.

What you probably don’t know: Many of us, right now, may be unintentionally overdosing on our medications.

The necessary restrictions of the drug regulatory system, coupled with a common desire of both health professionals and patients for an immediate effect, are part of the problem. Add to this the overall under-appreciation of, or the inability to predict, the huge variation in response that individual patients will exhibit to medications, and we have the perfect storm for the unintentional medication overdosing of a large segment of our population.

Before a drug is approved, drug companies have to show a medication has an “effect.” The significant regulatory and financial limitations in the drug discovery and approval process virtually dictate that the doses selected for study need to be at a level that will generate a response in most patients. In addition, initial studies are usually done on otherwise relatively healthy individuals who are least likely to run into problems.

As the late Lewis Sheiner, a clinical pharmacology guru, stated in 1991: “The dose studied is a dose almost guaranteed to be excessive.”

Once the preliminary studies have been completed, by regulation, the studied doses then become the initial marketed dose; it is also the dose that most health professionals will choose, since it is recommended in the product monograph.

Studies to determine the lowest effective dose are rarely done, and certainly not until well after a drug has been released onto the market.

Neither the drug industry, regulatory bodies nor health professionals are conspiring to promote overly high doses for patients. The problem is a systemic one: the end result of a sequence of events that invariably leads to an excessive initial dosage recommendation for most of our medications — as my colleagues and I pointed out in an article on the topic in the Canadian Medical Association Journal in January 2011.

There are any number of examples of studies, completed well after a medication has been approved, marketed and widely prescribed, that show the original recommended doses were higher than needed for many patients. Recent examples include doses for sildenafil for erectile dysfunction; bupropion for smoking cessation; ranitidine for heartburn; colchicine for gout; fluoxetine for depression; iron for anemia; many blood pressure medications; oral contraceptives; estrogen for menopausal symptoms; and inhaled steroids for asthma — just to name a few.

In some cases, as little as one-quarter or one-eighth of the original recommended dosage ends up being shown to be either equally effective or at least to provide an important benefit — with fewer side-effects.

The reverse hardly ever happens — recommendations to use higher doses of a medication after it has been released onto the market.

So, what’s the solution?

We could, and should, increase the level of post-market evaluations of medications with a specific focus on finding the lowest effective dose. As important as this measure might be, it would still be an after-the-fact solution and would only address part of the issue.

For the foreseeable future, we are left with the fact that initial dose recommendations for medications will often be higher than needed for many patients.

So how can you know what’s the best dose for you?

No matter what type of approval system is in place, or the number of studies completed on a medication before or after it hits the market, the truth is that no one will be able to know ahead of time the right dose and dosing interval specific for you. Only you, with the help of your medical provider, can figure that out.

Once you are on a medication, know that everything now becomes an experiment to determine the best dose.

Unless you have a condition that is severe or is immediately life-threatening, or you need a response from the very first dose, under the guidance of your medical provider, start with a very low dose (one-half to one-quarter of the marketed dose); you can then increase the dose slowly up to the “best” dose for you. This is a simple and potentially cost-saving approach that can’t help but lead to a reduced chance of side-effects, reduce many of the problems with drug interactions and, most importantly, give control back to the person taking the medication.

James McCormack is an expert adviser with EvidenceNetwork.ca and professor with the Faculty of Pharmaceutical Sciences at the University of British Columbia.

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Dose recommendations: A tough pill to swallow

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